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- Alijagic, Andi, 1992-, et al.
(författare)
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A Novel Nanosafety Approach Using Cell Painting, Metabolomics, and Lipidomics Captures the Cellular and Molecular Phenotypes Induced by the Unintentionally Formed Metal-Based (Nano)Particles
- 2023
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Ingår i: Cells. - : MDPI. - 2073-4409. ; 12:2
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Tidskriftsartikel (refereegranskat)abstract
- Additive manufacturing (AM) or industrial 3D printing uses cutting-edge technologies and materials to produce a variety of complex products. However, the effects of the unintentionally emitted AM (nano)particles (AMPs) on human cells following inhalation, require further investigations. The physicochemical characterization of the AMPs, extracted from the filter of a Laser Powder Bed Fusion (L-PBF) 3D printer of iron-based materials, disclosed their complexity, in terms of size, shape, and chemistry. Cell Painting, a high-content screening (HCS) assay, was used to detect the subtle morphological changes elicited by the AMPs at the single cell resolution. The profiling of the cell morphological phenotypes, disclosed prominent concentration-dependent effects on the cytoskeleton, mitochondria, and the membranous structures of the cell. Furthermore, lipidomics confirmed that the AMPs induced the extensive membrane remodeling in the lung epithelial and macrophage co-culture cell model. To further elucidate the biological mechanisms of action, the targeted metabolomics unveiled several inflammation-related metabolites regulating the cell response to the AMP exposure. Overall, the AMP exposure led to the internalization, oxidative stress, cytoskeleton disruption, mitochondrial activation, membrane remodeling, and metabolic reprogramming of the lung epithelial cells and macrophages. We propose the approach of integrating Cell Painting with metabolomics and lipidomics, as an advanced nanosafety methodology, increasing the ability to capture the cellular and molecular phenotypes and the relevant biological mechanisms to the (nano)particle exposure.
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| 2. |
- Alijagic, Andi, 1992-, et al.
(författare)
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Immunotoxic, genotoxic, and endocrine disrupting impacts of polyamide microplastic particles and chemicals
- 2024
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Ingår i: Environment International. - : Elsevier. - 0160-4120 .- 1873-6750. ; 183
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Tidskriftsartikel (refereegranskat)abstract
- Due to their exceptional properties and cost effectiveness, polyamides or nylons have emerged as widely used materials, revolutionizing diverse industries, including industrial 3D printing or additive manufacturing (AM). Powder-based AM technologies employ tonnes of polyamide microplastics to produce complex components every year. However, the lack of comprehensive toxicity assessment of particulate polyamides and polyamide-associated chemicals, especially in the light of the global microplastics crisis, calls for urgent action. This study investigated the physicochemical properties of polyamide-12 microplastics used in AM, and assessed a number of toxicity endpoints focusing on inflammation, immunometabolism, genotoxicity, aryl hydrocarbon receptor (AhR) activation, endocrine disruption, and cell morphology. Specifically, microplastics examination by means of field emission scanning electron microscopy revealed that work flow reuse of material created a fraction of smaller particles with an average size of 1-5 µm, a size range readily available for uptake by human cells. Moreover, chemical analysis by means of gas chromatography high-resolution mass spectrometry detected several polyamide-associated chemicals including starting material, plasticizer, thermal stabilizer/antioxidant, and migrating slip additive. Even if polyamide particles and chemicals did not induce an acute inflammatory response, repeated and prolonged exposure of human primary macrophages disclosed a steady increase in the levels of proinflammatory chemokine Interleukin-8 (IL-8/CXCL-8). Moreover, targeted metabolomics disclosed that polyamide particles modulated the kynurenine pathway and some of its key metabolites. The p53-responsive luciferase reporter gene assay showed that particles per se were able to activate p53, being indicative of a genotoxic stress. Polyamide-associated chemicals triggered moderate activation of AhR and elicited anti-androgenic activity. Finally, a high-throughput and non-targeted morphological profiling by Cell Painting assay outlined major sites of bioactivity of polyamide-associated chemicals and indicated putative mechanisms of toxicity in the cells. These findings reveal that the increasing use of polyamide microplastics may pose a potential health risk for the exposed individuals, and it merits more attention.
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| 3. |
- Angelov, Angel G., 1983-
(författare)
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Methods for interval-censored data and testing for stochastic dominance
- 2018
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- This thesis includes four papers: the first three of them are concerned with methods for interval-censored data, while the forth paper is devoted to testing for stochastic dominance.In many studies, the variable of interest is observed to lie within an interval instead of being observed exactly, i.e., each observation is an interval and not a single value. This type of data is known as interval-censored. It may arise in questionnaire-based studies when the respondent gives an answer in the form of an interval without having pre-specified ranges. Such data are called self-selected interval data. In this context, the assumption of noninformative censoring is not fulfilled, and therefore the existing methods for interval-censored data are not necessarily applicable.A problem of interest is to estimate the underlying distribution function. There are two main approaches to this problem: (i) parametric estimation, which assumes a particular functional form of the distribution, and (ii) nonparametric estimation, which does not rely on any distributional assumptions. In Paper A, a nonparametric maximum likelihood estimator for self-selected interval data is proposed and its consistency is shown. Paper B suggests a parametric maximum likelihood estimator. The consistency and asymptotic normality of the estimator are proven.Another interesting problem is to infer whether two samples arise from identical distributions. In Paper C, nonparametric two-sample tests suitable for self-selected interval data are suggested and their properties are investigated through simulations.Paper D concerns testing for stochastic dominance with uncensored data. The paper explores a testing problem which involves four hypotheses, that is, based on observations of two random variables X and Y, one wants to discriminate between four possibilities: identical survival functions, stochastic dominance of X over Y, stochastic dominance of Y over X, or crossing survival functions. Permutation-based tests suitable for two independent samples and for paired samples are proposed. The tests are applied to data from an experiment concerning the individual's willingness to pay for a given environmental improvement.
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